B Cells and IL-21-Producing Follicular Helper T Cells Cooperate to Determine the Dynamic Alterations of Premetastatic Tumor Draining Lymph Nodes of Breast Cancer.

Metastasis is the major cause of cancer-related death, and lymph node is the most common site of metastasis in breast cancer. However, the alterations that happen in tumor-draining lymph nodes (TDLNs) to form a premetastatic microenvironment are largely unknown. Here, we first report the dynamic changes in size and immune status of TDLNs before metastasis in breast cancer. With the progression of tumor, the TDLN is first enlarged and immune-activated at early stage that contains specific antitumor immunity against metastasis. The TDLN is then contracted and immunosuppressed at late stage before finally getting metastasized. Mechanistically, B and follicular helper T (Tfh) cells parallelly expand and contract to determine the size of TDLN. The activation status and specific antitumor immunity of CD8+ T cells in the TDLN are determined by interleukin-21 (IL-21) produced by Tfh cells, thus showing parallel changes. The turn from activated enlargement to suppressed contraction is due to the spontaneous contraction of germinal centers mediated by follicular regulatory T cells. On the basis of the B-Tfh-IL-21-CD8+ T cell axis, we prove that targeting the axis could activate TDLNs to resist metastasis. Together, our findings identify the dynamic alterations and regulatory mechanisms of premetastatic TDLNs of breast cancer and provide new strategies to inhibit lymph node metastasis.

Multi-omics study reveals different pathogenesis of the generation of skin lesions in SLE and IDLE patients.

Lupus erythematosus (LE) is a heterogeneous, antibody-mediated autoimmune disease. Isolate discoid LE (IDLE) and systematic LE (SLE) are traditionally regarded as the two ends of the spectrum, ranging from skin-limited damage to life-threatening multi-organ involvement. Both belong to LE, but IDLE and SLE differ in appearance of skin lesions, autoantibody panels, pathological changes, treatments, and immunopathogenesis. Is discoid lupus truly a form of LE or is it a completely separate entity? This question has not been fully elucidated. We compared the clinical data of IDLE and SLE from our center, applied multi-omics technology, such as immune repertoire sequencing, high-resolution HLA alleles sequencing and multi-spectrum pathological system to explore cellular and molecular phenotypes in skin and peripheral blood from LE patients. Based on the data from 136 LE patients from 8 hospitals in China, we observed higher damage scores and fewer LE specific autoantibodies in IDLE than SLE patients, more uCDR3 sharing between PBMCs and skin lesion from SLE than IDLE patients, elevated diversity of V-J recombination in IDLE skin lesion and SLE PBMCs, increased SHM frequency and class switch ratio in IDLE skin lesion, decreased SHM frequency but increased class switch ratio in SLE PBMCs, HLA-DRB1*03:01:01:01, HLA-B*58:01:01:01, HLA-C*03:02:02:01, and HLA-DQB1*02:01:01:01 positively associated with SLE patients, and expanded Tfh-like cells with ectopic germinal center structures in IDLE skin lesions. These findings suggest a significant difference in the immunopathogenesis of skin lesions between SLE and IDLE patients. SLE is a B cell-predominate systemic immune disorder, while IDLE appears limited to the skin. Our findings provide novel insights into the pathogenesis of IDLE and other types of LE, which may direct more accurate diagnosis and novel therapeutic strategies.

The development and initial validation of IgG4-related disease damage index: a consensus report from Chinese IgG4-RD Consortium.

OBJECTIVE: To develop and conduct an initial validation of the Damage Index for IgG4-related disease (IgG4-RD DI). METHODS: A draft of index items for assessing organ damages in patients with IgG4-RD was generated by experts from the Chinese IgG4-RD Consortium (CIC). The preliminary DI was refined using the Delphi method, and a final version was generated by consensus. 40 IgG4-RD cases representing four types of clinical scenarios were then selected, each with two time points of assessment for at least 3 years of follow-up. 48 rheumatologists from 35 hospitals nationwide were invited to evaluate organ damage using the CIC IgG4-RD DI. The intraclass correlation coefficient (ICC) and the Kendall-W coefficient of concordance (KW) were used to assess the inter-rater reliability. The criterion validity of IgG4-RD DI was tested by calculating the sensitivity and specificity of raters. RESULTS: IgG4-RD DI is a cumulative index consisting of 14 domains of organ systems, including a total of 39 items. The IgG4-RD DI was capable of distinguishing stable and increased damage across the active disease subgroup and stable disease subgroup. In terms of scores at baseline and later observations by all raters, overall consistency in scores at baseline and later observations by all raters was satisfactory. ICC at the two time points was 0.69 and 0.70, and the KW was 0.74 and 0.73, respectively. In subgroup analysis, ICC and KW in all subgroups were over 0.55 and 0.61, respectively. The analysis of criterion validity showed a good performance with a sensitivity of 0.86 (95% CI 0.82 to 0.88), a specificity of 0.79 (95% CI 0.76 to 0.82) and an area under the curve of 0.88 (95% CI 0.85 to 0.91). CONCLUSION: The IgG4-RD DI is a useful approach to analyse disease outcomes, and it has good operability and credibility. It is anticipated that the DI will become a useful tool for therapeutic trials and studies of prognosis in patients with IgG4-RD.

The role of epithelial cells in the immunopathogenesis of Sjögren's syndrome.

Sjögren's syndrome is a systemic autoimmune disease characterized by dysfunction of the affected exocrine glands. Lymphocytic infiltration within the inflamed glands and aberrant B-cell hyperactivation are the two salient pathologic features in Sjögren's syndrome. Increasing evidence indicates that salivary gland epithelial cells act as a key regulator in the pathogenesis of Sjögren's syndrome, as revealed by the dysregulated innate immune signaling pathways in salivary gland epithelium and increased expression of various proinflammatory molecules as well as their interaction with immune cells. In addition, salivary gland epithelial cells can regulate adaptive immune responses as nonprofessional antigen-presenting cells and promote the activation and differentiation of infiltrated immune cells. Moreover, the local inflammatory milieu can modulate the survival of salivary gland epithelial cells, leading to enhanced apoptosis and pyroptosis with the release of intracellular autoantigens, which further contributes to SG autoimmune inflammation and tissue destruction in Sjögren's syndrome. Herein, we reviewed recent advances in elucidating the role of salivary gland epithelial cells in the pathogenesis of Sjögren's syndrome, which may provide rationales for potential therapeutic targeting of salivary gland epithelial cells to alleviate salivary gland dysfunction alongside treatments with immunosuppressive reagents in Sjögren's syndrome.

FAR in systemic lupus erythematosus: a potential biomarker of disease activity and lupus nephritis.

The fibrinogen-to-albumin ratio (FAR), a novel inflammatory marker, has been studied in various diseases. However, the significance of FAR in systemic lupus erythematosus (SLE) has not been fully elucidated. This study was to investigate the connection between FAR and SLE. A retrospective analysis of 154 SLE patients and 77 healthy individuals was performed. The clinical and laboratory data were reviewed. Receiver operating characteristic (ROC) curves were conducted for FAR at baseline to predict disease activity and lupus nephritis (LN) in SLE patients. Pearson correlation was also applied. FAR in the SLE group was found to be significantly higher than that of the healthy control group (83.71 mg/g vs. 53.14 mg/g, P < 0.001). It was also significantly higher in patients with LN than that in patients without (107.64 mg/g vs. 67.75 mg/g, P < 0.001). The ROC curve for predicting LN showed that the area under the curve (AUC) of FAR (0.859, 95% CI 0.803-0.914) was the largest when compared to albumin (0.852, 95% CI 0.789-0.916) or fibrinogen (0.736, 95% CI 0.659-0.814) alone. In addition, FAR was a good predictor of severe disease activity in SLE (AUC = 0.721, 95% CI 0.612-0.830) and LN patients (AUC = 0.789, 95% CI 0.680-0.898). Pearson correlation analysis indicated that FAR demonstrated a strong correlation with SLE disease activity index 2000 (r = 0.4288, P < 0.001). FAR was significantly increased in SLE patients. It is a possible biomarker for disease activity and renal involvement in SLE.

Dauricine regulates prostate cancer progression by inhibiting PI3K/AKT-dependent M2 polarization of macrophages.

M2 type tumor-associated macrophages, an essential component of the tumor microenvironment (TME), have been proved to contribute to tumor metastasis. Dauricine (Dau) has recently received widespread attention due to its multiple targets and low price. However, the effect of Dau on macrophage polarization of TME remains unclear. In this study, we investigated the effect of Dau on prostate cancer (PCa) metastasis and specifically its correlation to macrophage polarization. Our results showed that Dau efficiently suppressed M2 polarization of macrophages induced by interleukin (IL) -4 and IL-13. Mechanistically, Dau inhibited the activity of PI3K/AKT signaling pathway, which subsequently suppressed macrophage differentiation to M2 type. Importantly, our study indicated that Dau decreased the release of chitinase 3-like protein 1 (CHI3L1) from M2 macrophages, which ultimately inhibited the M2 macrophage-mediated progression of PCa cells in vitro and in vivo. Taken together, our data demonstrated that Dau suppressed M2 polarization of macrophages via downregulation of the PI3K/AKT signaling pathway, in turn, preventing proliferation, epithelial-mesenchymal transition, migration, and invasion of PCa cells. Thus, this study reveals a previously unrecognized function of Dau in inhibition of PCa progression via intervention in M2 polarization of macrophages.

Exosome inspired photo-triggered gelation hydrogel composite on modulating immune pathogenesis for treating rheumatoid arthritis.

Although exosome therapy has been recognized as a promising strategy in the treatment of rheumatoid arthritis (RA), sustained modulation on RA specific pathogenesis and desirable protective effects for attenuating joint destruction still remain challenges. Here, silk fibroin hydrogel encapsulated with olfactory ecto-mesenchymal stem cell-derived exosomes (Exos@SFMA) was photo-crosslinked in situ to yield long-lasting therapeutic effect on modulating the immune microenvironment in RA. This in situ hydrogel system exhibited flexible mechanical properties and excellent biocompatibility for protecting tissue surfaces in joint. Moreover, the promising PD-L1 expression was identified on the exosomes, which potently suppressed Tfh cell polarization via inhibiting the PI3K/AKT pathway. Importantly, Exos@SFMA effectively relieved synovial inflammation and joint destruction by significantly reducing T follicular helper (Tfh) cell response and further suppressing the differentiation of germinal center (GC) B cells into plasma cells. Taken together, this exosome enhanced silk fibroin hydrogel provides an effective strategy for the treatment of RA and other autoimmune diseases.

Jmjd1c demethylates STAT3 to restrain plasma cell differentiation and rheumatoid arthritis.

Appropriate regulation of B cell differentiation into plasma cells is essential for humoral immunity while preventing antibody-mediated autoimmunity; however, the underlying mechanisms, especially those with pathological consequences, remain unclear. Here, we found that the expression of Jmjd1c, a member of JmjC domain histone demethylase, in B cells but not in other immune cells, protected mice from rheumatoid arthritis (RA). In humans with RA, JMJD1C expression levels in B cells were negatively associated with plasma cell frequency and disease severity. Mechanistically, Jmjd1c demethylated STAT3, rather than histone substrate, to restrain plasma cell differentiation. STAT3 Lys140 hypermethylation caused by Jmjd1c deletion inhibited the interaction with phosphatase Ptpn6 and resulted in abnormally sustained STAT3 phosphorylation and activity, which in turn promoted plasma cell generation. Germinal center B cells devoid of Jmjd1c also acquired strikingly increased propensity to differentiate into plasma cells. STAT3 Lys140Arg point mutation completely abrogated the effect caused by Jmjd1c loss. Mice with Jmjd1c overexpression in B cells exhibited opposite phenotypes to Jmjd1c-deficient mice. Overall, our study revealed Jmjd1c as a critical regulator of plasma cell differentiation and RA and also highlighted the importance of demethylation modification for STAT3 in B cells.

CDKN3 Overcomes Bladder Cancer Cisplatin Resistance via LDHA-Dependent Glycolysis Reprogramming.

Background: Aerobic glycolysis plays an important role in bladder cancer (BLCA) progression and chemoresistance. Cyclin-dependent kinase inhibitor-3 (CDKN3), a dual-specificity protein tyrosine phosphatase, has aberrant upregulation in multiple cancer types and is associated with tumorigenesis. However, the role of CDKN3 in BLCA progression and glycolysis has not been elucidated. Purpose: In this study, we investigated the effect and underlying mechanisms of CDKN3 on bladder cancer chemoresistance. Results: This study confirmed that CDKN3 was overexpressed in BLCA tissues and promoted proliferation and migration. Additionally, our results showed a CDKN3-dependent mechanism on chemoresistance; chemoresistance cells were transformed into chemosensitivity cells by CDKN3 knockdown. Additionally, we showed that CDKN3 knockdown decreased glycolysis by inhibiting LDHA expression in BLCA chemoresistance cells. The results also proved that LDHA was an important mediator of CDKN3-regulated BLCA resistance. LDHA overexpression reversed glycolysis inhibition and chemosensitivity induced by CDKN3 downregulation. Conclusion: These data collectively identified a vital role of CDKN3 in glycolysis and chemoresistance by regulating LDHA expression in BLCA cells, providing a possible therapeutic strategy for treating BLCA.

Landscape of the Peripheral Immune Response Induced by Local Microwave Ablation in Patients with Breast Cancer.

Minimally invasive thermal therapies have been attempted in the treatment of breast cancer, and the immune response induced by these therapies has not been fully reported. A clinical trial is performed to determine the effect of microwave ablation (MWA) in the treatment of early-stage breast cancer. The authors perform single-cell RNA sequencing on peripheral blood mononuclear cells (PBMCs) from six patients before and after ablation. NK and CD8+ T cells are activated by MWA of breast cancer, with the increased inhibitory signature of CD8+ T cells but not dysfunctional. Enhanced co-stimulatory signature of CD4+ T cells is observed and increased frequency of ICOS+ CD4+ T cells after MWA is confirmed by flow cytometric analysis. After ablation, T-cell clones expand with increased T-cell receptor diversities. Activated antigen receptor-mediated signaling pathways are found in B cells. Enhanced interactions between B cells and CD4+ T cells are found, indicating that B cells are important antigen-presenting cells that initiate CD4+ T cells in MWA-induced immune response. Blockade of CTLA-4 or PD-1 of post-MWA PBMCs show higher T-cell activity than that of pre-MWA PBMCs. This study provide global characteristics of MWA-induced systemic immune response and pave a way for the identification of potential targets to improve the immune response.

B7-H4 expression promotes non-small cell lung cancer progression via AMPK/mTOR signaling.

Several studies have demonstrated that B7-H4 is highly expressed in a variety of cancers and often affects tumor development. However, its role in cancer stemness and epithelial-to-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC) has not been reported. Here, we investigated the relationship between B7-H4 expression and cancer stemness and EMT by immunohistochemistry in 106 NSCLC tissues obtained from patients. The results confirmed that B7-H4 is highly expressed in NSCLC tissues and closely correlated with the expression of EMT-related proteins (Snail, Vimentin) and cancer stemness-related proteins (SOX2, SOX9, and CD44). Immunofluorescence assay indicated that B7-H4 colocalized with SOX2 and SOX9 in the nuclei of NSCLC cells. Additionally, upon knocking down B7-H4, the expression of SOX2, SOX9, and CD44, as well as of Snail and Vimentin was inhibited, whereas E-cadherin expression was enhanced in NSCLC cells. Meanwhile, inhibiting the expression of B7-H4 resulted in reduced invasion and migration ability of NSCLC cells. Mechanistically, silencing B7-H4 activated the adenosine monophosphate-activated protein kinase /mammalian target of rapamycin signaling, which in turn, negatively regulated cell proliferation, stemness, and migration. In conclusion, our results suggest that B7-H4 expression is high in NSCLC tissues, and it has an effect on EMT and cancer stemness. This further suggests that B7-H4 has a potential role in promoting the progression of NSCLC and thereby could be a potential therapeutic target in NSCLC treatment.

SETD5 Regulates Glycolysis in Breast Cancer Stem-Like Cells and Fuels Tumor Growth.

Although glycolysis plays a pivotal role in breast cancer stem-like cell (BCSC) reprogramming, the molecular mechanisms that couple glycolysis to cancer stem-like cells remain unclear. SETD5 is a previously uncharacterized member of the histone lysine methyltransferase family. The goal of this study was to explore the mechanisms underlying the promotion of stem-like and glycolysis activation traits by SETD5. Previous studies have shown that overexpression of SETD5 in breast cancer tissues is associated positively with progression. The present study showed that SETD5 expression was enriched in BCSCs. Down-regulation of SETD5 significantly decreased BCSC properties and glycolysis in vitro and in vivo. Interestingly, SETD5 and glycolytic enzymes were accumulated in the central hypoxic regions of subcutaneous tumor tissues. Bioinformatic analysis predicted SETD5 binding to E1A binding protein p300 (EP300), and subsequently to hypoxia-inducible factor 1α (HIF-1α). The mechanistic study found that SETD5 is an upstream effector of EP300/HIF-1α. SETD5 knockdown reduced the expression of HIF-1α, hexokinase-2, and 6-phosphofructo-2-kinase in the nucleus after treatment with cobalt chloride, a chemical hypoxia mimetic agent that activates HIF-1α to accumulate in the nucleus. Therefore, SETD5 is required for glycolysis in BCSCs through binding to EP300/HIF-1α and could be a potential therapeutic target for breast cancer patients.

Blockade of adiponectin receptor 1 signaling inhibits synovial inflammation and alleviates joint damage in collagen-induced arthritis.

OBJECTIVES: Adiponectin (AD) highly expressed in synovial tissue correlates closely with progressive bone erosion in rheumatoid arthritis (RA). However, it remains unknown whether AD receptor mediates the pathogenesis of RA. This study aimed to investigate the effects of adiponectin receptor 1 (AdipoR1) signaling on synovial inflammation and joint damage in collagen-induced arthritis. METHODS: AD and AdipoR1 expression in synovial tissue of RA and osteoarthritis (OA) patients were tested by PCR and western blotting. The frequency of AdipoR1 on RA synovial fibroblasts (RASFs) was examined by flow cytometry after stimulation with AD, IL-6, or TNF-α. AdipoR1 was knocked down in human RASF cell line (MH7A) and CIA mice joints using lentiviral particles carrying the AdipoR1 short hairpin RNA (shAdipoR1). Both the proliferation and apoptosis of MH7A and the secretion of inflammatory factors from MH7A were examined in vitro. The therapeutic effect of local AdipoR1 inhibition on CIA mice was assessed in vivo. RESULTS: Both the expression of AD and AdipoR1 were significantly higher in RA synovial tissue. AdipoR1 on RASFs was upregulated by AD. Silencing AdipoR1 remarkably reduced lipopolysaccharides-induced proliferation and promoted the apoptosis of MH7A. Moreover, AdipoR1 knockdown inhibited the release of inflammatory factors in vitro. In CIA mice, local AdipoR1 inhibition effectively decreased joint inflammation and alleviated bone destruction via suppressing RANKL and RANKL/OPG ratio in vivo. CONCLUSIONS: AdipoR1 signaling participates in the process of synovial inflammation and joint damage in CIA. Local blockade of AdipoR1 might be a new target for the clinical treatment of RA. Key points • Local AdipoR1 inhibition decreased joint inflammation and alleviated bone destruction in CIA.

B10 cells decrease fibrosis progression following cardiac injury partially by IL-10 production and regulating hyaluronan secretion.

B10 cells play negative roles in inflammatory disorders by producing IL-10. However, their effects on fibrosis have not been elucidated. Therefore, this study was conducted to examine the dynamic changes of B10 cell frequency and their potential role in cardiac fibrosis. We found that the frequency of B10 cells was significantly increased, and they participated in the regression of fibrosis via IL-10, particularly by accelerating hyaluronan secretion and inhibiting collagen deposition. In vivo, hyaluronan ablation or treatment significantly restricted cardiac fibrosis development. hyaluronan-induced conversion of M1/M2 Mc was dependent on the size of hyaluronan. Low molecular weight hyaluronan promoted the conversion to M1 Mϕ, whereas medium and high molecular weight hyaluronan accelerated Mϕ transdifferentiation into the M2 phenotype. Adoptive transfer of B10 cells significantly attenuated collagen deposition whereas CD19-/- mice with reduced B10 cells exacerbated fibrosis following cardiac injury. Our results provide new evidence suggesting that B10 cells exert antifibrotic effects by regulating the extracellular matrix composition during cardiac injury, and also highlight that B10 cells may serve as a promising therapeutic candidate for managing cardiac fibrosis-associated disorders.

Correlation of peripheral CD4+GranzB+CTLs with disease severity in patients with primary Sjögren's syndrome.

INTRODUCTION: Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune disease which has focal lymphocytic infiltration including a majority of CD4+ T cells. This study was to investigate the correlation of peripheral granzyme B (GranzB)-expressing CD4+ T cells with disease severity and histological lesion in patients with pSS. METHODS: We recruited 116 pSS and 46 health control (HC) using flow cytometry to examine the percentage of CD4+GranzB+CTLs in the peripheral blood, and immunofluorescence to test their expression in the labial gland. RESULTS: The percentage of CD4+GranzB+CTLs was significantly upregulated in pSS than in HC (7.1 ± 4.9% vs 3.1 ± 1.9%, p < 0.0001) and positive correlation with ESSDAI. The frequency of them was markedly higher in pSS with extraglandular manifestations. After excluding the other risk factors associated with pSS, they were still related to ESSDIA and extraglandular manifestations independently (p < 0.05), and they are the risk factor of extraglandular involvement (odds ratio = 1.928). Moreover, they could be observed in the LSGs. ROC curve analysis indicated that the area under the curve (AUC) of CD4+GranzB+CTLs was 0.796 to predict the activity of pSS and 0.851 to presume extraglandular manifestations. The best diagnostic cutoff point was 4.865 for pSS patients. CONCLUSION: In this study, we provide new evidence indicating the involvement of CD4+GranzB+CTLs over activation in the pathophysiology of pSS, which may serve as a new biomarker to evaluate the activity and severity of pSS.

Guideline for the diagnosis, treatment and long-term management of cutaneous lupus erythematosus.

Cutaneous lupus erythematosus (CLE) is an inflammatory, autoimmune disease encompassing a broad spectrum of subtypes including acute, subacute, chronic and intermittent CLE. Among these, chronic CLE can be further classified into several subclasses of lupus erythematosus (LE) such as discoid LE, verrucous LE, LE profundus, chilblain LE and Blaschko linear LE. To provide all dermatologists and rheumatologists with a practical guideline for the diagnosis, treatment and long-term management of CLE, this evidence- and consensus-based guideline was developed following the checklist established by the international Reporting Items for Practice Guidelines in Healthcare (RIGHT) Working Group and was registered at the International Practice Guideline Registry Platform. With the joint efforts of the Asian Dermatological Association (ADA), the Asian Academy of Dermatology and Venereology (AADV) and the Lupus Erythematosus Research Center of Chinese Society of Dermatology (CSD), a total of 25 dermatologists, 7 rheumatologists, one research scientist on lupus and 2 methodologists, from 16 countries/regions in Asia, America and Europe, participated in the development of this guideline. All recommendations were agreed on by at least 80% of the 32 voting physicians. As a consensus, diagnosis of CLE is mainly based on the evaluation of clinical and histopathological manifestations, with an exclusion of SLE by assessment of systemic involvement. For localized CLE lesions, topical corticosteroids and topical calcineurin inhibitors are first-line treatment. For widespread or severe CLE lesions and (or) cases resistant to topical treatment, systemic treatment including antimalarials and (or) short-term corticosteroids can be added. Notably, antimalarials are the first-line systemic treatment for all types of CLE, and can also be used in pregnant patients and pediatric patients. Second-line choices include thalidomide, retinoids, dapsone and MTX, whereas MMF is third-line treatment. Finally, pulsed-dye laser or surgery can be added as fourth-line treatment for localized, refractory lesions of CCLE in cosmetically unacceptable areas, whereas belimumab may be used as fourth-line treatment for widespread CLE lesions in patients with active SLE, or recurrence of ACLE during tapering of corticosteroids. As for management of the disease, patient education and a long-term follow-up are necessary. Disease activity, damage of skin and other organs, quality of life, comorbidities and possible adverse events are suggested to be assessed in every follow-up visit, when appropriate.

HBXIP accelerates glycolysis and promotes cancer angiogenesis via AKT/mTOR pathway in bladder cancer.

Abnormal metabolism and uncontrolled angiogenesis are two important characteristics of malignant tumors. Although HBXIP is known to be associated with a poor prognosis for bladder cancer (BC), its effects on glycolysis and angiogenesis in BC have not been investigated. BC prognosis and relative gene expression of HBXIP were analyzed using the GEPIA, UALCAN, and STRING databases. BC cell angiogenesis and glycolysis were assessed by vasculogenic mimicry and glycolysis assay. Human umbilical vein endothelial cell (HUVEC) viability, migration, and angiogenesis were assessed by CCK8, transwell, wound healing, and tube formation assays. The results showed that HBXIP was highly expressed in BC tissues and cells. Knockdown of HBXIP expression decreased the levels of glucose uptake, lactate production, and glycolytic enzyme expression in BC cells, and decreased cell viability and migration of HUVECs. Additionally, silencing HBXIP reduced the total length of tubes and number of intersections, and EPO and VEGF protein expression in BC cells and HUVECs. Furthermore, knockdown of HBXIP expression reversed cell viability, migration, tube formation, and vasculogenic mimicry under high glucose and lactate conditions. Mechanistically, silencing of HBXIP reduced the protein expression levels of pAKT-ser473 and pmTOR, and inhibition of HBXIP, AKT, and mTOR expression decreased glycolytic enzyme protein expression. Our findings suggest that HBXIP reduces glycolysis in BC cells via regulation of AKT/mTOR signaling, thereby blocking BC angiogenesis. Collectively, this study provides a potential strategy to target HBXIP and AKT/mTOR for regulating glycolysis progression concurrently with anti-angiogenesis effects, and thereby develop novel therapeutics for the treatment of BC.

The Multiple Roles of B Cells in the Pathogenesis of Sjögren's Syndrome.

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease characterized by lymphocytic infiltration and tissue destruction of exocrine glands such as salivary glands. Although the formation of ectopic lymphoid tissue in exocrine glands and overproduction of autoantibodies by autoreactive B cells highlight the critical involvement of B cells in disease development, the precise roles of various B cell subsets in pSS pathogenesis remain partially understood. Current studies have identified several novel B cell subsets with multiple functions in pSS, among which autoreactive age-associated B cells, and plasma cells with augmented autoantibody production contribute to the disease progression. In addition, tissue-resident Fc Receptor-Like 4 (FcRL4)+ B cell subset with enhanced pro-inflammatory cytokine production serves as a key driver in pSS patients with mucosa-associated lymphoid tissue (MALT)-lymphomas. Recently, regulatory B (Breg) cells with impaired immunosuppressive functions are found negatively correlated with T follicular helper (Tfh) cells in pSS patients. Further studies have revealed a pivotal role of Breg cells in constraining Tfh response in autoimmune pathogenesis. This review provides an overview of recent advances in the identification of pathogenic B cell subsets and Breg cells, as well as new development of B-cell targeted therapies in pSS patients.

Adiponectin Enhances B-Cell Proliferation and Differentiation via Activation of Akt1/STAT3 and Exacerbates Collagen-Induced Arthritis.

Although B cells have been shown to contribute to the pathogenesis of rheumatoid arthritis (RA), the precise role of B cells in RA needs to be explored further. Our previous studies have revealed that adiponectin (AD) is expressed at high levels in inflamed synovial joint tissues, and its expression is closely correlated with progressive bone erosion in patients with RA. In this study, we investigated the possible role of AD in B cell proliferation and differentiation. We found that AD stimulation could induce B cell proliferation and differentiation in cell culture. Notably, local intraarticular injection of AD promoted B cell expansion in joint tissues and exacerbated arthritis in mice with collagen-induced arthritis (CIA). Mechanistically, AD induced the activation of PI3K/Akt1 and STAT3 and promoted the proliferation and differentiation of B cells. Moreover, STAT3 bound to the promoter of the Blimp-1 gene, upregulated Blimp-1 expression at the transcriptional level, and promoted B cell differentiation. Collectively, we observed that AD exacerbated CIA by enhancing B cell proliferation and differentiation mediated by the PI3K/Akt1/STAT3 axis.